In a report of a case recently published in the journal Dr Emerging Infectious Diseases, researchers describe a neurologic disease caused by pigeon avian paramyxovirus type 1 (PPMV-1) that led to the death of an immunocompromised toddler in Australia. They found hypothesis-free metagenomic testing to be a useful tool for diagnosing unspecified etiologies, such as in this case.
Research: Fatal human neurological infection caused by pigeon avian paramyxovirus-1, Australia. Image credit: THANAN KONDOUNG / Shutterstock
Avian paramyxovirus type 1 (APMV-1) is a single-stranded RNA virus known to cause Newcastle disease, an infectious disease in birds with neurological, digestive and respiratory manifestations. In humans, this zoonotic disease usually manifests as mild conjunctivitis and is rarely fatal. In the present case, researchers report neurologic disease caused by a pigeon variant of APMV-1 (PPMV-1), primarily spread by pigeons and doves, resulting in the death of an immunocompromised pediatric patient.
A 2-year-old female with a history of pre-B cell acute lymphoblastic leukemia (ALL), treated with blinatumomab six months earlier, developed nausea and vomiting after three weeks of upper respiratory symptoms. Six weeks ago he underwent a second round of reinduction chemotherapy with 6-mercaptopurine, cytarabine and cyclophosphamide. There was no history of exposure to illness, pets or travel. As his condition improved over the next four days, he developed infection-related epilepsy syndrome (FIS) in February.
Initial magnetic resonance imaging (MRI) of the cerebrum was unremarkable. Tests for autoimmune encephalitis were negative. Significant inflammation was observed in the central nervous system (CNS) as indicated by high levels of neurotropin (1,752 nmol/L) in the cerebrospinal fluid. Exome sequencing results did not suggest any genetic abnormalities. Culture and polymerase chain reaction (PCR) tests revealed no bacterial, fungal, viral, or mycobacterial pathogens.
Magnetic resonance imaging of the brain in an immunocompromised infant with avian paramyxovirus type 1 infection in Australia. Image taken 16 days after hospitalization, showing predominantly left frontal and insular T2 signal hyperintensity developing laminar necrosis (white arrow) and hyperintensity of deep gray matter structures (red arrow).
A brain biopsy followed by hematoxylin and eosin staining of specimens, performed 20 days after admission, revealed extensive cortical necrosis with limited subpial sparing. with gliosis rather than foamy macrophages and scattered CD3-positive T-cell cortex. Viral inclusions, microglial nodes or viral cytopathic effects were found to be absent. NeuN immunostaining indicates sparse residual small neurons. It is important to note that no viral pathogens were detected in CSF, plasma, or brain tissue, ruling out several viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Negative results were obtained for bacterial and fungal culture, pan-mycobacterial PCR and 16S ribosomal ribonucleic acid (RNA) PCR.
Despite immunomodulators, antimicrobials, antiseizure drugs, and a ketogenic diet, the patient’s condition did not improve. An MRI taken two weeks later demonstrated progressive and diffuse inflammatory changes, characterized by increased hyperintensity on the left frontal and insular T2 signals, progressing to laminar necrosis. Additionally, T2 hyperintensity was observed in deep gray-matter structures.
Treatment was discontinued, and the patient expired 27 days after hospitalization. Although not performed postmortem, extensive agnostic metagenomic testing and unbiased meta-transcriptomic sequencing were performed in parallel on biopsied brain tissue. The results revealed a dominant presence of human pagivirus (HPgV) as a viral strain of APMV-1 and a low level of non-human sequences. Phylogenetic analysis suggested that the virus originated from a putative Australian lineage of PPMV-1, belonging to class II, genotype VI, sublineage 220.127.116.11.2.
Virus-specific quantitative PCR and immunohistochemistry were used to confirm APMV-1 infection in tissue samples. Nucleoprotein clustered cells and pyramidal neurons were observed in sample tissues and no staining was detected in negative controls (adolescent brain and lymphoid tissue).
Previous studies have highlighted the virulence and severe disease potential of PPMV-1 compared to other APMV-1 genotypes. Because HPGV has not been known to be associated with human disease so far, and no other infections have been found, the encephalitis patient’s death was attributed to PPMV-1 infection in the CNS. Given the respiratory symptoms observed in the child, it is suggested that the upper respiratory tract infection started after inadvertent exposure to infected pigeon feces or fluids.
This is the first report identifying an association between FIRES and avian viruses. Because AMPV-1 has previously been used as an oncolytic agent, the current study recommends that researchers carefully consider the virulence of different strains of this virus and the potential adverse effects of using PPMV-1.
In summary, this case highlights the complex interplay between prior leukemia treatment, infectious triggers, and neurological complications in pediatric patients. It demonstrates the significance of using metagenomics in identifying new pathogens, diagnosing complex clinical cases, and simplifying overall workflows. However, the integration of metagenomics into routine diagnostics is limited by its cost and the need for skilled labor. Further research and development to address these challenges may help increase the accessibility and affordability of this technique, thereby improving patient health outcomes in emerging infectious diseases.